Numerous investigations have shown that orexin-containing neurons that arise within the hypothalamus are critical regulators of sleep and feeding processes. In addition, very recent findings have implicated orexin systems in drug-seeking behaviors. For example, previous studies in our laboratory have shown that the orexin-1 receptor antagonist, SB-334867, blocked stress-induced reinstatement of extinguished cocaine responding in rats. Therefore, the blockade of orexin-1 receptors may be an effective strategy for the treatment of substance abuse disorders. However, the role of orexin-1 receptors in regulating the reinforcing effects of nicotine has not been assessed. Here, the first aim of this application will be to evaluate the effects of SB-334867 on the reinforcing effects of nicotine. To accomplish this task, the PI will utilize intravenous self-administration and intracranial self-stimulation procedures in well-trained rats to determine if SB-334867 decreases nicotine consumption and abolishes the stimulatory effects of nicotine on brain reward systems. The second aim of this proposal will be to identify neuroanatomical substrates of the brain reward system that regulate nicotine reinforcement via orexin-1 receptors. Specifically, the PI will microinfuse SB-334867 into the bed nucleus of the stria terminalis (BNST) or ventral tegmental area (VTA) to determine if blockade of orexin-1 receptors in these areas decreases nicotine intake in rats. While SB- 334867 certainly antagonizes the orexin-1 receptor, it is derived from a class of compounds that has high affinity for other non-orexin receptor classes as well. Indeed, it is presently unclear if SB-334867 acts only at orexin-1 receptors, or has 'off-target'effects at other receptor classes that may confound interpretation of data using this compound. Therefore, the third aim will directly assess the importance of the orexin-1 receptor in nicotine reinforcement by evaluating the acquisition of intravenous nicotine self-administration in orexin-1 receptor knockout mice compared with wildtype littermates. Collectively, these studies will provide important insights into psychobiological mechanisms of nicotine dependence processes, and promise to yield a novel therapeutic strategy for the treatment for human nicotine addiction. The devastating personal, social and economic cost of nicotine addiction has generated much research into understanding how the brain processes drug reward, and has motivated efforts to develop novel treatment strategies for treating the disorder. The experiments presented in this application investigate the role of orexin-1 receptors in nicotine reinforcement in rats and mice. Based on our preliminary research, blockade of orexin receptors may be a viable strategy to aid smokers who wish to quit their habit.